Method of making alkyldihydrothebainones



Patented June 6, 1950 METHQD or. MAKING ALKYLDIHYDRO-- EBAINQNES.

Frank C. Whitmore, State College, Pa., and August H. Homeyer.Webster-Groves, Md, assigncrs to Mellinc rod h micat Works. St. Louis,Mo. a corporation of Missouri No Drawing. Application May 3, 1946,Serial No. 66?,108

V 9 Claims. (01.

This invention. relates to the. manufacture. of narcotics and morearticularly to. methodsior them-operation of intermediates for. themanu-. iacture of methyldihydromorphinone.

Among the objects of this inventionaare the provision or methods, forthe. utilization. of byproducts in the manufacture of derivativesof themorphine, series; the provision of .methods for improving the yield ofdesired products in the manufacture of derivatives of; the morphineseries; and theprovision of methods. for more easily preparingintermediates for themanufacture of: methyldihydromorphinona.. Otherob-.- jects willbe in part apparent and inpart pointed out. hereinafter.

The invention accordingly comprises the steps and sequence of steps, andfeatures ofsynthesis, analysis, or metathesis, which will; be.exemplifled. in the processes hereinafter described, and the. scope ofthe application of which. wilLbe-indicated in the following. claims.

In the manufacture of. methyldihydroinon. phinone. one of the,intermediates customarily, utilized; is. methyldihydrothebainone. This.in: termediate may be. prepared from thebaine by hydrogenation todihydrothebaine, followed by reaction with a. Grignard reagent. toformin'ethe yldihydrothehainone It' has been found, hows ever, that onhydrogenation of thebaine, relatively small. quantities ofdihydrothebaineiv are. obtained. together with larger quantities ofvdihydrothebainone.

Dihydrotheoainone has. been of'limited utility because to convert.ittothe desired methyldihy-- drothebainone ithasbeennecessary-toifirstform dihydrocodeinone, then the acetate or the enol'forinof dihydrocodeinone, and then to form the desired methylderivative, methyldihydrothebainone.-

In accordance with the-present invention, however, it has been foundthat dihydrocodeinonecan be directly converted tomethyldihydrothebainone without the intermediate formation,

to methyl-dihydrothebainoneby formation, for" example, of the acetylderivative of'thezenol form:

of dihydrocodcinone, followed by reaction of this product with aGrignard reagent, are materially shortened and improved.

The following examples illustrate the invention:

Example I Two molesof methyl magnesium iodide solution. (1310. cc. of.1.53 N), was distilled in a 5 liter,

three-necked flask fitted with amercury sealed stirrer, dropping funneland condenser, until no more other came over with the bath at about C.One liter of. dry benzene was added to the residue, stirred, and heatedto boiling, while a solution of 290 g. of dihydrocodeinone in 2 litersof dry benzene was added during 10 minutes. Distillation was continuedby heating until 800 cc. of distillate were collected. Then thecondenser was set for refluxing which was continued for 3 six hours. Avoluminous white solid formed during the addition of thedihydrocodeinone to th'e Grignard reagent. At the end of the reaction,the'complex was decomposed by adding to the flask excess dilutehydrochloric acid (about 350 1 cc. concentrated hydrochloric aciddiluted to 2 liters) and the benzene layer was separated and washed withdilute hydrochloric acid'whichwasadded-to the main aqueous phase. Theaqueous phase-was stirred with 1 liter of chloroform and ammonia-cal byadding a small excess of" 1 1.1 g, or"4:7-% of the theoreticalyield;

Example II itizruetherv solution. of-206cc. ofmethyl mag l cur 580 cc.portions of chloroform and the" inedextracts were distilled to dryness.The methyldihydrothebainone' nesium bromide containing 0.4 mole wasconcentrated by distillation in a water bath until no more ether woulddistill. 270 cc. of dry benzene was added and the condenser was arrangedfor refluxing. After bringing to refluxing temperature, a warm solutionof 40 grams of dihydrocodeinone in 700 cc. of dry benzene was addedduring 18 minutes. The solution was stirred and refluxed for one andone-half hours and then was refluxed without stirring for four and onehalf hours more. A test for the presence of a Grignard reagent wasnegative. The reaction mixture was decomposed by addition of excessdilute hydrochloric acid and then the solution was made alkaline withammonia, and a little sodium hydrosulfite, NazSzOi, was added. Thebenzene layer was separated and the Water layer was extracted threetimes with chloroform. The benzene and chloroform extracts werecombined, dried, and concentrated by distillation, the last traces ofsolvent being removed under reduced pressure. The residue, weighing 32.5grams, was dissolved in 60 cc. of anhydrous alcohol and the solution wassaturated with hydrogen chloride. A precipitate formed immediately andafter storing in a refrigerator overnight, it was filtered off andwashed with alcohol. The dry methyldihydrothebainone hydrochlorideweighed 15.5 grams.

In the foregoing examples other methyl magnesium halides may besubstituted for the methyl magnesium iodide and methyl magnesium bromiderespectively described.

ExampZe III 12 grams of impure methyldihydrothebainone was suspended in100 cc. of Water and dissolved by adding hydrobromic acid until all thesolid was in solution and the solution was acid to Congo. The solutionwas decolorized with activated carbon and allowed to crystallize. Thecrystals of methyldihydrothebainone hydrobromide after drying weighed12.6 grams.

Example IV 72.5 grams of crude methyldihydrothebainone hydrochloride wasdissolved in 300 cc. of hot water, decolorized with activated carbon andafter filtering, 40 grams of sodium bromide was added.Methyldihydrothebainone hydrobromide crystallized rapidly. After coolingit was filtered off and washed with alcohol. The slightly moisthydrobromide weighed 71 grams.

As shown in these examples the hydrobromide of methyldihydrothebainonecan be prepared by reacting the alkaloid with hydrobromic acid or it canbe formed by treating the hydrochloride of the alkaloid with a bromidesalt. The hydrobromide is of particular value. For example, it has moredesirable solubility characteristics than the hydrochloride, and isaccordingly of a special utility for purifying the alkaloid.

It will be understood, of course, that homologs ofmethyldihydrothebainone may be prepared in an analogous manner by usingan appropriate Grignard reagent.

The extraction of the crude methyldihydrothebainone is advantageouslycarried out by the use of chloroform as indicated in the foregoingexamples. chloroform is not only an efiective solvent for this purpose,but it has certain advantages over the previously utilized solvents. Forexample, extraction with ether is hazardous and clumsy on account of thelarge volumes of solvent required. Extraction with benzene has atendency to form stubborn emulsions. Chloroform as a solvent for thispurpose is not subject to the foregoing disadvantages. Relatively smallproportions of chloroform are effective to extract themethyldihydrothebainone efiiciently from its aqueous solution.

In view of the above, it will be seen that the several objects of theinvention are achieved and other advantageous results attained.

As many changes could be made in the above processes without departingfrom the scope of the invention, it is intended that all mattercontained in the above description shall be interpreted as illustrativeand not in a limiting sense.

We claim:

1. The method of making an alkyldihydrothebainone which comprises addingdihydrocodeinone to a Grignard reagent selected from the groupconsisting of an alkyl magnesium bromide and an alkyl magnesium iodidein an aromatic solvent.

2. The method of making methyldihydrothebainone which comprises addingdihydrocodeinone in an aromatic solvent to a methyl Grignard reagentselected from the group consisting of a methyl magnesium bromide and amethyl magnesium iodide in an aromatic solvent.

3. The method of making methyldihydrothebainone which comprises addingdihydrocodeinone to a methyl Grignard reagent selected from the groupconsisting of a methyl magnesium bromide and a methyl magnesium iodidein benzene.

4. The method of making methyldihydrothebainone which comprises addingdihydrocodeinone in benzene to a methyl Grignard reagent selected fromthe group consisting of a methyl magnesium bromide and a methylmagnesium iodide in benzene.

5. The method of making methyldihydrothebainone which comprises removingthe major portion of the solvent ether from an ethereal solution of amethyl Grignard reagent selected from the group consisting of a methylmagnesium bromide and a methyl magnesium iodide, adding an aromaticsolvent to said Grignard reagent and then adding dihydrocodeinone.

6. The method of making methyldihydrothebainone which comprises adding abenzene solution of dihydrocodeinone to a benzene solution of a methylmagnesium halide selected from the group consisting of a methylmagnesium bromide and a methyl magnesium iodide, decomposing the complexformed by adding excess dilute hydrochloric acid, extracting themethyldihydrothebainone with chloroform, purifying the product byforming a hydroha-lide of the methyldihydrothebainone.

7. The method of making an alkyldihydrothebainone which comprisesreacting dihydrocodeinone with a Grignard reagent selected from thegroup consisting of an alkyl magnesium bromide and an alkyl magnesiumiodide in an aromatic solvent.

8. The. method of making an alkyldihydrothebainone which comprisesreacting dihydrocodeinone with an alkyl magnesium bromide and anaromatic solvent.

9. The method of making an alkyldihydrothebainone which comprisesreacting dihydrocodeinone with alkyl magnesium iodide and an aromaticsolvent.

FRANK C. WHITMO-RE. AUGUST H. HOMEYER.

(References on following page) REFERENCES ormn OTfiER REFERENCES Thefollowing references are of record in the vLutz at ,1,: J. Am. Chem.Soc., vol. 57, pp. 265ifile of this patent: 2656 (1935).

' Sm 11 t 1.: J. .Ch .SOc., 1.58, .1457- UNITED STATES PATENTS 5 14 3 Aug. 1936) em v0 pp Gilman: Organic Chemistry (John Wiley New Number NameDate 2,178,010 Small et a1 Oct 31. 1939 York, 1938), vol. I, pp. 109,110 and 556.

Fieser and Fieser: Organic Chemistry (D. C. 2'364'833 Wemard 1 10Heath'& Co., 1944; Boston); p. 39 and p.803.

6. THE METHOD OF MAKING METHYLDIHYDROTHEBAINONE WHICH COMPRISES ADDING ABENZENE SOLUTION OF DIHYDROCODEINONE TO A BENZENE SOLUTION OF A METHYLMAGNESIUM HALIDE SELECTED FROM THE GROUP CONSISTING OF A METHYLMAGNESIUM BROMIDE AND A METHYL MAGNESIUM IODIDE, DECOMPOSING THE COMPLEXFORMED BY ADDING EXCESS DILUTE HYDROCHLORIC ACID, EXTRACTING THEMETHYLDIHYDROTHEBAINONE WITH CHLOROFORM, PURIFYING THE PRODUCT BYFORMING A HYDROHALIDE OF THE METHYLDIHYDROTHEBAINONE.